Project Summary/Abstract Depression is a chronic, impairing form of psychopathology that is one of the world's leading causes of disability. An extensive literature on the neural mechanisms of depression has documented the disruption of function in reward circuitry as part of the pathophysiology of depression. Specifically, frontostriatal function is altered, with lower ventral striatal (VS) response, greater medial prefrontal cortex (mPFC) response, and stronger functional connectivity between the two regions. Yet few neuromodulatory approaches to depression have targeted this circuitry. Noninvasive neuromodulatory techniques such as transcranial magnetic stimulation (TMS) have been applied to depression and can elucidate the pathophysiology of this disorder by focusing on function in frontostriatal circuitry. For the proposed R21 study, we will conduct a within-subject, counterbalanced study using interleaved functional MRI and TMS to examine the acute effects of theta-burst stimulation (TBS, a briefer form of TMS) to dmPFC in 35 young adults (18-25 years, 50% female) with depression. Each participant will undergo 2 sessions, one each of intermittent and continuous TBS, with the goal of increasing or decreasing dmPFC responding, respectively. Brain function, behavior, and mood will be assessed before and after each TBS session. Broadly, we predict that inhibitory TBS of the dmPFC will reduce dmPFC function and dmPFC-VS connectivity. We will also assess the potential for such change in frontostriatal circuitry to alter behavioral and subjective aspects of reward function, such as positive mood. The proposed study takes a circuit-based perspective and uses a multi-level assessment approach with the goal of identifying biomarkers of affective psychopathology. Its goal is to manipulate positive valence systems at the neural level to understand their function, and potentially reveal a source of heterogeneity relevant to future research in experimental therapeutics. Its high level of innovation and early stage of development for understanding this circuit using this method make it ideally suited for R21 funding.